This Mentored Research Scientist Development Proposal describes a four-year research and career development program in the field of metabolomics, with a focus on gaining better understanding of metabolic mechanisms of fuel-stimulated insulin secretion and peripheral insulin resistance. The candidate, Dr. Jessica Gooding, aims to launch an independent career as the director of an analytical core with an emphasis on metabolomics and systems biology. Her research program and mentorship team will provide the training necessary to 1) build mastery in a variety of metabolomics techniques and related statistical methods in the context of complex biological systems 2) develop business and communication skills relevant to directing a core facility and 3) successfully compete for positions and NIH funding. The Stedman Nutrition and Metabolism Center at Duke University, which includes a metabolomics core facility, provides a stimulating environment conducive to meeting these goals. An advisory committee of Dr. Christopher B. Newgard (Mentor), Deborah M. Muoio (Co-mentor), Xianlin Han (Co-mentor). Matthew Hirschey, Svati Shah, James Bain, and Robert Stevens will provide mentorship and expertise in the areas of insulin secretion, insulin resistance, lipidomics, sirtuin biology, biostatistics, and metabolomics method development and laboratory management, respectively. The research plan aims to 1) expand on my current repertoire of techniques; 2) complete two mechanistic studies utilizing targeted techniques with the purpose of (a) understanding the mechanism of changes in purine metabolite levels as a result of glucose stimulated insulin secretion (GSIS), and (b) characterizing the energy state of models of insulin resistance and impaired exercise endurance; and 3) leverage this repertoire of metabolomics techniques to understand the metabolic link between sirtuin proteins and insulin secretion. Preliminary data supports each of these aims. Each of these mechanistic studies have the potential to identify new pathways involved in insulin secretion and glucose intolerance and lead to new targets for control of diabetes.